Dr. Mengyin Cai

Hjelt grant holder 2011, Lund university

Epigenetic changes in diabetic nephropathy (DN)

Dr. Mengyin Cai, PhD, received a postdoctoral fellowship from the Foundation February 2011 to December 2012. Dr. Cai obtained her PhD in Sun Yat-sen University, China, working on “molecular mechanism on lamin C deficiency related lypodystrophic diabetes”. She started her Hjelt Foundation-funded funded project in Prof. Leif Groop’s group, focusing on epigenetic changes in diabetic nephropathy (DN). DN is one of the most devastating diabetic complications and the leading cause of renal failure in developed countries. Although hyperglycemia represents the most important risk factor for development of diabetic vascular complications, not all hyperglycemic patients seem to be at equal risk. Based upon observations in two large studies on T1D and T2D, DCCT and UKPD, the term “metabolic memory” was introduced to describe the long term effects of initial good or poor metabolic control for protection of or susceptibility to diabetic complications in both T1D and T2D. While genetic factors have been suggested to contribute to DN susceptibility in addition to the elevated glucose, results from genetic studies have thus far been disappointing. It suggests other factors modify an indivdual’s susceptibility to develop complications. One possible reason could be epigenetic mechanism including histone modifications. Dr. Cai’s project tested effect of glucose on expression of two proinflammatory genes, thioredoxin-interacting protein (TXNIP) and ostepontin (OPN), which both have been ascribed a role in the pathogenesis of DN in cell lines and animal models. She found that hyperglycemia induced active TXNIP and OPN genes expression, increased H3K9 acetylation (activating histone marks) and reduced H3K27 trimethylation (H3K27me3) (inactivating histone marks) in normal human mesangial cells. In a diabetes-prone mouse model (a mouse model with knock-in of a human mutation in the Sur-1 gene), she further identified the more coordinated changes in histone marks, TXNIP and OPN genes expression in kidneys in response to the longer exposure to hyperglycemia. These results demonstrate the impact of glucose on histone modifications, which contributes to two proinflammatory genes: TXNIP and OPN expression may be association with development of DN. The research data is included in a manuscript to soon be submitted.

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